1,7-Dihydro-pyrrolo[3,4-e][1,4]diazepin-2(1H)-one derivatives

ABSTRACT

1,7-Dihydro-pyrrolo[3,4-e][1,4]diazepin-2(1H)-ones of the formula ##STR1## wherein R is lower alkyl, R 1  stands for hydrogen, methyl, ethyl or phenyl, R 2  is hydrogen or lower alkyl and R 3  is hydrogen, chloro, fluoro, bromo, trifluoromethyl or methoxy are described with anticonvulsant and anti-anxiety activity. 
     Also described is the process for preparing the above compounds and pharmaceutical preparations containing them.

The present invention refers to new pyrrolo-diazapine derivatives withanticonvulsant and anti-anxiety activity, to the process for preparingthem, the intermediates for their synthesis, and to the pharmaceuticalcompositions containing the new compounds.

The new pyrrolodiazepine derivatives which are the first object of thepresent invention have the following general formula ##STR2## wherein Rrepresents methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl, and 1,1-dimethylethyl, R₁ stands for hydrogen, methyl,ethyl, or phenyl, R₂ is hydrogen, methyl, ethyl, propyl, 1-methylethyl,butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl, and R₃represents hydrogen, chloro, fluoro, bromo, trifluoromethyl and methoxy.

The new pyrrolodiazepines of the present invention are useful ananticonvulsant and anti-anxiety agents.

A preferred group of compounds comprises those compounds of formula Iwherein R is methyl, R₁ is hydrogen, R₂ stands for hydrogen or methyl,and R₃ represents hydrogen, chloro, or fluoro.

A most preferred group comprises those compounds of formula I wherein Ris methyl, R₁ is hydrogen, R₂ stands for hydrogen or methyl and R₃represents hydrogen or chloro.

1,4-Diazepines fused on a pyrrole ring are described in Belgian Pat. No.826,925. These compounds differ structurally from those of the presentinvention in the presence of a methylene group instead of a ##STR3##group at the 3-position. Pharmacologically, the introduction of ahydroxy function at C-3 gives rise to a class of compounds unexpectedlymore active as anticonvulsant and anti-anxiety agents than the mostclosely related prior-art compounds bearing a hydrogen atom at C-3,considerably less toxic, and surprisingly devoid of inducing activity.

The new compounds of the present invention are prepared starting from aN-(4-aroyl-5-methyl-(1H)pyrrol-3-yl) 2-iodoacetamide of formula II##STR4## wherein R, R₁, R₂, and R₃ are as defined above, through amulti-step synthesis involving:

(a) reaction with hydroxylamine to give anN-(4-aroyl-5-methyl-(1H)pyrrol-3-yl) 2-hydroxylaminoacetamide III##STR5##

(b) cyclization of the obtained intermediate to yield an N-oxide offormula IV ##STR6##

(c) rearrangement of this latter compound by treatment with aceticanhydride to a 3-acetoxy-pyrrolo[3,4-e][1,4]diazepine V ##STR7##followed by

(d) mild alkaline hydrolysis to the desired end compound of formula I.

In the actual practice the first step of the reaction scheme seen above,i.e. the reaction of the iodoacetamide derivative with hydroxylamine, iscarried out by reacting the iodoacetamide derivative with an excess ofhydroxylamine, preferably prepared in situ by adding an alkali metalhydroxide to an aqueous solution of hydroxylamine hydrochloride, in alower alkanol.

When the reaction, which is followed by thin layer chromatography, iscomplete, the intermediate hydroxylaminoacetamide III is recoveredaccording to conventional procedures which involve for instanceevaporation of the reaction solvent and washing of the obtained residue,or strong dilution of the reaction mixture with salted water andrecovery of the precipitate formed. If desired, the compound thusobtained, is purified by crystallization or it may be used as such inthe second step of the reaction, the cyclization to N-oxide. Saidcyclization passes through two steps. In the first one, thehydroxylaminoacetamide derivative III is converted into an intermediatediazepinium salt of formula VI ##STR8## by heating, and preferablyrefluxing, a suspension of the hydroxylaminoacetamide derivative III ina lower alkanol in the presence of a strong acid HX. Acids which mayconveniently be employed in this step can be hydrochloric, sulfuric,methanesulfonic and the like acids. In the second step, the intermediatediazepinium salt, recovered by crystallization from the alcoholicsolvent, is transformed, with or withoug previous characterization, intothe N-oxide IV by treatment with aqueous bases such as alkali metalhydroxides or carbonates in aqueous solutions. Rearrangement of theN-oxide IV with acetic anhydride smoothly takes place by suspending theN-oxide IV in acetic anhydride at room temperature. In general, howeverthe reaction mixture is heated for a few minutes in order to completethe reaction. The resulting 3-acetoxy derivative V, which is recoveredby crystallization from the reaction solvent, is then submitted to mildalkaline hydrolysis yielding the desired end compound of formula I. Thishydrolytic step may simply be carried out by heating the 3-acetoxyderivative V with an equimolar amount of an alkali metal hydroxide inaqueous alcoholic solvents. Furthermore, when a compound of formula I isdesired wherein R₂ is a lower alkyl group, it may be prepared alsostarting from a compound II wherein R₂ is hydrogen, and submittingeither the 3-acetoxy intermediate V or the N-oxide IV, obtained byfollowing the process described above, to common alkylation proceduresbefore further processing these intermediates as seen above.

In the former case the reaction is conveniently carried out bycontacting the 3-acetoxy intermediate with an alkyl halide R₂ X whereinR₂ is a lower alkyl group as defined above and X stands for chloro,bromo or iodo, in the presence of a strong base such as an alkali metalamide, hydride, hydroxide or alkoxide, and once the alkylation reactionis complete, by adding water to bring out the deacetylation. In thelatter case, i.e. when the alkylation reaction is carried out on theN-oxides IV, it is more conveniently carried out in aqueous alkali. Thestarting iodoacetamide derivatives of formula II are easily preparedfrom the corresponding chloroacetamide derivatives VII ##STR9## throughreaction with an alkali metal iodide in ethanol or acetone according tothe Finkelstein reaction. In their turn the chloroacetamide derivativesVII are prepared through reaction of chloroacetic acid chloride with a3-aroyl-4-aminopyrrole compound of formula VIII ##STR10## wherein R, R₁,R₂, and R₃ have the same meanings as above. These latter compounds canbe obtained by alkylation at the pyrrole nitrogen atom, and optionallyat the amine nitrogen atom also, of the corresponding3-aroyl-4-aminopyrrole derivative VIII wherein R and R₂ are hydrogenprepared by reacting an α-aminonitrile of formula ##STR11## with aβ-diketone of formula ##STR12## according to conventional procedures.

A further specific object of the present invention is the intermediatesof formula IV and V obtained in the above synthetic pathway.

The novel compounds of the present invention as well as theintermediates of formula IV and V possess anticonvulsant andanti-anxiety activity.

To evaluate the anticonvulsant activity the compounds of the presentinvention have been submitted to the antipentylenetetrazole bioassay inmice. The experiments have been carried out by following essentially themethodology described by Berger in J. Pharm. Exptl. Ther. 104, 468,(1952). More particularly, a fatal dose of pentylenetetrazole (140 mg/kgs.c.) was administered to groups of ten mice each, treated, 30 minutesbefore the administration of the convulsant agent, with a selected doseof the potential anticonvulsant compound. One of these groups, the"control" group, did not receive the anticonvulsant but only theconvulsant agent. Since the animals of the control group died within 30minutes, the effectiveness of the compounds tested, at each dose tested,was expressed as the number of animals of the group which were stillalive two hours after the administration of pentylenetetrazole, out ofthe total number of animals of the group (10).

By testing each compound at different doses, the corresponding ED₅₀,i.e. the dose at which 50% of the treated animals are protected, wascalculated. The results obtained in these experiments are reported inthe following Table A.

                  TABLE A                                                         ______________________________________                                        Compound of example No.                                                                         ED.sub.50 mg/kg os                                          ______________________________________                                         9                7.5                                                         10                7.5                                                         11                5                                                           ______________________________________                                    

The same test was carried out also with3,7-dihydro-6,7-dimethyl-5-phenyl-pyrrol[3,4-e][1,4]diazepin-2 (1H)-one(IX) ##STR13##

This compound, which is the most active compound of the class ofpyrrolodiazepines described in Belgian Pat. No. 826,925, showed to be atleast twice less active than the compounds of the present inventionsince its ED₅₀ calculated in the same way as for the compounds of thepresent invention, is 15 mg/kg/os.

The anti-anxiety activity of the compounds of the present invention wasfirst shown by submitting the compounds to the "benzodiazepinereceptors" test both in vitro and in vivo. It was recently discovered infact that there exist specific binding sites for benzodiazepines in thecentral nervous system which act in mediating the anxiolytic propertiesof benzodiazepines, and it was demonstrated (see for instance S. Lippaet al., Pharmacol. Biochem. & Behaviour, Vol. 9, 853-856 (1978) and H.Moler and T. Okada, Brit. J. Psychiat., 133, 261-68 (1978)) that theability of a substance to displace ³ H-Diazepam from its specific ratbrain receptors, both in vitro and in vivo, is significantly correlatedwith its anxiolytic properties.

The in vitro experiments were carried out by following the methoddescribed by H. Moler and T. Okada in Life Sciences Vol. 20, 2101-2110(1977) while those in vivo were carried out according to the proceduresillustrated by S. Lippa et al. in Pharmacol. Biochem. & Behaviour, Vol.9, pp. 853-856 (1978).

The results obtained in these tests with some representative compoundsof the present invention and with3,7-dihydro-6,7-dimethyl-5-phenylpyrrolo[3,4-e][1,4]diazepin-2-(1H)-one,the compound known from Belgian Pat. No. 826,925, are summarized in thefollowing Table B.

                  TABLE B                                                         ______________________________________                                        Compound of example      "in vivo" % inhibition                               No.          "in vitro" Ki                                                                             at 1 mg/kg/os                                        ______________________________________                                        5            45.9 × 10.sup.-9                                                                    -45                                                  11           2.82 × 10.sup.-9                                                                    -54                                                  3,7-dihydro-6,7-dime-                                                         thyl-5-phenylpyrrolo-                                                         [3,4-e][1,4]diazepin-                                                         2(1H)-one      97 × 10.sup.-9                                                                    -33                                                  ______________________________________                                    

The anxiolytic activity of the compounds of the present invention wasthen confirmed by the results obtained in other experiments in animals.More particularly the ability of the compounds of the present inventionto increase punished responding in a conflict situation, a procedurewith high validity for predicting the anxiolytic effect of drugs, wasassessed by testing these compounds in rats according to the methoddescribed by I. Geller and J. Seifter in Psychopharmacologia 1, 482,(1960). Briefly, in this test, rats are trained to press a lever inorder to get a food reward, and each rat exhibits a characteristic andrather stable rate of lever pressing. During an audible signal of a fewminutes duration that is occasionally presented, each press of the leverwill provide a food reward but will be accompanied by a brief electricshock. A situation of conflict between the rat's desire for food and hisfear of the shock soon develops. The rate of lever pressing during thepunished period, in the absence of drug treatment, is highly reduced,and each rat develops a characteristic response pattern during theconflict period.

The experiments carried out showed that the compounds of the presentinvention, when administered by the oral route to these trained animals,were able to remarkably increase rat's responses during the conflictperiod at doses which did not influence the characteristic rate of leverpressing during the non-conflict portion.

Another behavioural test which confirmed the anti-anxiety properties ofthe compounds of the present invention was the so-called "taming effect"test carried out on naturally vicious and aggressive monkeys.

The "taming effect" on monkeys is one of the most meaningful andreliable parameters with which the anti-anxiety properties of a compoundcan be investigated. A drug supposed to be an anti-anxiety but not aCNS-depressant agent must in fact relieve the animals from anxiety butlet them react normally to the external stimuli, i.e. it must alter theanimals' naturally hostile and aggressive behaviour at doses at whichCNS-depressant side-effects do not occur. A true "taming effect", as anindication of the anti-anxiety properties of a compound not ascribableto CNS-depression, is reached when the animals become docile andfriendly so as to accept food from the observer's hand. In this test,the compounds of examples 10 and 11 of the present invention, at theoral dose of 1 mg/kg, displayed a true "taming effect" in at least 50%of the treated animals. Furthermore, the compounds of the presentinvention, unlike the prior-art compounds, showed to be devoid ofinducing activity.

More particularly while the3,7-dihydro-6,7-dimethyl-5-phenylpyrrolo[3,4-e][1,4]diazepin-2(1H)-onedescribed in Belgian Pat. No. 826,925 potentiated the "sleeping time"induced by hexobarbital in rats starting from 1 mg/kg p.o., thecompounds of examples 5 and 11 of the present invention, tested in thesame conditions, did not show this potentiating effect even at higherdoses. This is considered as an indication of the absence of inducingactivity. These favorable pharmacological properties of the compounds ofthe present invention are accompanied by a low toxicity, lower than thatof the prior-art compounds. As an example, while the acute oral toxicityof the prior-art3,7-dihydro-6,7-dimethyl-5-phenylpyrrolo[3,4-e][1,4]diazepin-2(1H)-onein mice is about 500 mg/kg, that of the compound of example 5 of thepresent invention is comprised between 600 and 700 mg/kg and that of thecompound of example 11 is higher than 20,000 mg/kg.

In view of the above, the use of the compounds of the present inventionas anticonvulsant and anti-anxiety agents, is a further specific objectof the present invention.

With the term "use" it is intended to refer to all industriallyapplicable aspects and acts of said use, including the embodiment of thenovel compounds into pharmaceutical compositions.

Suitable pharmaceutical compositions contain the novel compounds inadmixture or conjunction with organic or inorganic, solid or liquidpharmaceutical excipients and may be employed for enteral and parenteraladministration. Suitable excipients are substances that do not reactwith the new compounds such as for instance, water, gelatin, lactose,starches, magnesium stearate, talcum, vegetable oils, benzyl alcohol,polyalkyleneglycols, or other known medicinal excipients. The newcompounds may be administered by various routes: orally, intramuscularlyor intravenously, for example. For oral administration the substancesare compounded in such forms, as tablets, dispersible powders, capsules,granules, syrups, elixirs and solutions. For intravenous orintramuscular administration the active ingredients are embodied intoinjectable dosage forms. Such compositions are formulated as known inthe art.

The dosage regimen for the compounds of the present invention in accordwith anticonvulsant, anti-anxiety treatment will depend upon a varietyof factors including the particular compound used, the route ofadministration, and the type of treatment applied for. Good results canbe obtained however by administering the compounds of the presentinvention at a daily dosage range comprised between about 0.05 and about3 mg/kg preferably in divided doses. It is however clear that a dailydosage beyond the above indicated range may also be employed dependingon the individual conditions of the subject to be treated.

Accordingly the present invention provides a therapeutic compositioncontaining from about 2.5 to about 150 mg of one of the compounds of theinvention as the active ingredient together with a pharmaceuticallyacceptable carrier.

Following are illustrative pharmaceutical formulations which may beemployed in practicing the present invention:

    ______________________________________                                                             Per Tablet                                               ______________________________________                                        Preparation of a tablet formulation:                                          5-(2-chlorophenyl-1,7-dihydro-3-hydroxy-                                      1,6,7-trimethylpyrrolo[3,4-e][1,4]diazepin-                                   2(1H)-one              25        mg                                           starch                 25        mg                                           Aerosil ® V 200    1.25      mg                                           magnesium stearate     1         mg                                           lactose                q.s. to 180                                                                             mg                                           Preparation of a capsule formulation                                          5-(2-chlorophenyl)-1,7-dihydro-3-hydroxy-                                     6,7-dimethylpyrrolo[3,4-e][1,4-]diazepin-                                     2(1H)-one              20        mg                                           starch                 20        mg                                           magnesium stearate     1         mg                                           lactose                q.s. to 180                                                                             mg                                           ______________________________________                                    

The following examples describe in details some of the compounds of theinvention and illustrate the process for preparing them without limitingthe scope of the present invention.

EXAMPLE 1 N-(4-benzoyl-1,5-dimethyl(1H)pyrrol-3-yl)-2-hydroxylaminoacetamide

Sodium hydroxide (64 g) was added to a solution of hydroxylaminehydrochloride (111 g) in water (370 ml) and the obtained solution wasdiluted with ethanol (3500 ml). N-(4-benzoyl-1,5-dimethyl(1H)pyrrol-3-yl)-2-iodoacetamide (124.5 g) was then added and theobtained suspension was stirred under nitrogen stream for about 48hours. The reaction mixture was filtered in order to remove the saltsand the filtrate was concentrated to dryness at the pump. The residuewas washed with a small amount of water and crystallized from ethylacetate yielding 82.5 g of the compound of the title. M.p. 140°-42° C.

EXAMPLE 21,2,3,7-tetrahydro-4-hydroxy-6,7-dimethyl-2-oxo-5-phenyl-pyrrolo[3,4-e][1,4]diazepiniumchloride

The compound of example 1 (79.4 g) was suspended in isopropanolcontaining 2.1% of HCl (3700 ml) and refluxed for 2 hours with stirring.The reaction mixture was then cooled to 0° C. and a first crop (61 g) ofthe compound of the title which crystallized out was recovered byfiltration. A second crop (9 g) was obtained by concentrating the motherliquors to a small volume. M.p. 220°-223° C. with decomposition.

EXAMPLE 31,7-Dihydro-6,7-dimethyl-5-phenyl-pyrrole[3,5-e][1,4]diazepin-2(1H)-one-4-oxide

The compound of example 2 (140 g) was dissolved in water (1400 ml), theobtained solution was cleared by filtration and brought to pH 9 by theaddition of Na₂ CO₃ with stirring. NaCl (400 g) was then added to thesuspension, and stirring was continued for further 60 minutes. Thecompound of the title which precipitated was then recovered byfiltration (113 g). M.p. 255°-258° C.

EXAMPLE 4 3-Acetoxy-1,7-dihydro-6,7-dimethyl-5-phenyl-pyrrolo[3,4-e][1,4]diazepin-2(1H)-one

The compound obtained in Example 3 was suspended in acetic anhydride(500 ml) and the temperature of the reaction raised to 75° C. in a fewminutes. The reaction mixture was heated to 85° C. for 20 minutes withstirring then it was cooled to 0° C. and the crystalline precipitate wasrecovered yielding 117 g of the compound of the title. M.p. 255°-56° C.

EXAMPLE 51,7-Dihydro-3-hydroxy-6,7-dimethyl-5-phenyl-pyrrolo[3,4-e][1,4]diazepin-2(1H)-one

To a suspension of the compound of Example 4 (40 g) in ethanol (2000ml), cooled to 5° C., 1N NaoH (128 ml) was added with stirring. After 10minutes the reaction mixture was cooled to about 4° C. and allowed tostand at this temperature for one night. Then CO₂ was gradually added tothe solution to lower the pH to about 8. Ethanol was evaporated off atthe pump and the obtained residue was washed first with water and thenwith methanol, and crystallized from ethanol yielding 30 g of thecompound of the title. M.p. 243° C. with decomposition.

EXAMPLE 61,7-Dihydro-3-hydroxy-1,6,7-trimethyl-5-phenyl-pyrrolo[3,4-e][1,4]diazepin-2(1H)-one

The compound of Example 4 (25 g) was gradually added to a suspension ofsodium amide prepared from sodium (2.2 g) in liquid ammonia (900 ml),and the mixture was stirred for 30 minutes. Then methyl iodide (40 ml)was dripped into the mixture and stirring was continued until completeevaporation of ammonia. The reaction mixture was then diluted with waterand the oily suspension was extracted with ethyl acetate. The ethylacetate solution was washed with water, dried, and concentrated todryness. The residue was finally crystallized from ethanol yielding 10.5g of the compound of the title. M.p. 179°-81° C.

EXAMPLE 7 N-[4-(2-chlorobenzoyl)-1,5-dimethyl(1H)pyrrol-3-yl)]2-hydroxylaminoacetamide

The compound of the title was prepared by following essentially theprocedures described in example 1 but prolonging the reaction time to 72hours. The compound of the title was then recovered by diluting thereaction mixture with water (5 times the initial volume) containing NaCl(5.5 kg) and filtering the precipitate which crystallized out. M.p.166°-68° C. with decomposition.

EXAMPLE 85-(2-Chlorophenyl-1,7-dihydro-6,7-dimethyl-pyrrolo[3,4-e][1,4]diazepin(1H)-one-4-oxide

Methansulfonic acid (38 ml) was added to a suspension of the compound ofthe preceding example (137 g) in ethanol (3000 ml) and the reactionmixture was refluxed for 11 hours. The solvent was then evaporated offat the pump and the residue was taken up with water. The solution wasalkalinized with Na₂ CO₃, salted with NaCl and extracted with ethylacetate. The organic extract was dried over Na₂ SO₄ and concentrated todryness yielding a raw residue which was washed with ether andcrystallized from ethanol/ether yielding 115 g of the compound of thetitle. M.p. 220° C. with decomposition.

EXAMPLE 95-(2-chlorophenyl)-3-acetoxy-1,7-dihydro-6,7-dimethylpyrrolo[3,4-e][1,4]diazepin-2-(1H)-one

The compound of the title was prepared by following the proceduredescribed in example 4 but starting from the compound of the foregoingexample. M.p. 244°-46° C. Yield 59.5%.

EXAMPLE 105-(2-Chlorophenyl)-1,7-dihydro-3-hydroxy-6,7-dimethylpyrrolo[3,4-e][1,4-diazepin-2(1H)-one

The compound of the title was prepared by following essentially theprocedure described in Example 5 but starting from the compound ofExample 9. M.p. 201°-203° C.

EXAMPLE 115-(2-Chlorophenyl)-1,7-dihydro-3-hydroxy-1,6,7-trimethylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one

By following the procedure described in Example 6 but starting from thecompound of Example 9 the compound of the title was obtained. M.p.178°-80° C.

EXAMPLE 12 5-(2-chlorophenyl)-1,7-dihydro-6,7-dimethylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one-4-oxide

A suspension ofN-[4-(2-chlorobenzoyl)-1,5-dimethyl(1H)-pyrrol-3-yl]2-hydroxylaminoacetamide(130 g) in a solution of sulfuric acid (250 ml) in water (2400 ml) washeated to 80° C. for 1 hour. The reaction mixture was cooled to 20° C.,cleared by filtration, diluted with water (1500 ml) and filtered again.The acidic solution was then cautiously alkalinized by the addition ofNa₂ CO₃ and extracted with chloroform. By concentrating the organicextracts to dryness under vacuum at room temperature, 80 g of thecompound of the title were recovered.

EXAMPLE 135-(2-chlorophenyl-1,7-dihydro-1,6,7-trimethylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one-4-oxide

A solution of NaOH (27 g) in water (4700 ml) was added with stirring to5-(2-chlorophenyl)-1,7-dihydro-6,7-dimethylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one-4-oxide(165 g) finely suspended in ethanol (940 ml).

Then, dimethylsulfate (54.7 ml) was added during 10 minutes keeping thetemperature at about 20° C. The reaction mixture was stirred at thistemperature for 2 hours, then the insoluble was separated by undervacuum filtration. The clear solution was salted with NaCl and extractedwith chloroform. The organic extract was dried over Na₂ SO₄, andconcentrated to dryness under vacuum at 25°-30° C. The residue waswashed with ethyl ether yielding 135 g of the compound of the title.M.p. 198°-200° C. (from isopropanol).

EXAMPLE 143-Acetoxy-5-(2-chlorophenyl)-1,7-dihydro-1,6,7-trimethylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one

The compound of Example 13 (160 g) was suspended in acetic anhydride(660 ml) and the reaction flask was dipped in a water-bath at 55° C.After stirring for 15 minutes the reaction mixture was concentrated todryness under vacuum, and the obtained residue was taken up with boilingethanol and treated with charcoal.

By concentrating to a volume of 600 ml and cooling, the compound of thetitle (103 g) crystallized out. M.p. 202°-4° C.

EXAMPLE 155-(2-chlorophenyl)-1,7-dihydro-3-hydroxy-1,6,7-trimethylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one

1N NaOH (557 ml) was added to a suspension of3-acetoxy-5-(2-chlorophenyl)-1,7-dihydro-1,6,7-trimethylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one(200 g) in ethanol (1500 ml) keeping the temperature between 0 and 5° C.After stirring at 5° C. for 1 hour the suspension was gradually pouredinto a solution of NaCl (2 kg) in water (7500 ml), and the precipitatewhich formed was recovered by under vacuum filtration and washed firstwith water, and then with cold methanol yielding 160 g of the compoundof the title. Further 17 g were obtained by extracting the filtrate withethyl acetate and evaporating off the extracting solvent. M.p. 182°-83°C. (from ethyl acetate).

Preparation of the starting iodoacetamide derivative II EXAMPLE 16N-(4-benzoyl-1,5-dimethyl(1H)pyrrol-3-yl)-2-iodoacetamide

(a) 4-amino-3-benzoyl-2-methylpyrrole:

Aminoacetonitrile (0.04 mole) and benzoyl acetone (0.04 mole) wererefluxed for four hours in 30 ml of anhydrous benzene in the presence of100 mg of p-toluensulfonic acid. After cooling the reaction mixture wasfiltered and the solvent was evaporated off to give an oily residuewhich was dissolved in an ethanol solution containing sodium ethoxide(0.041 mole). The mixture was allowed to stand for 12 hours at roomtemperature and the solid precipitate which forms was recovered byfiltration.

(b) N-(4-benzoyl-5-methyl(1H)pyrrol-3-yl)2-chloroacetamide:

4-Amino-3-benzoyl-2-methylpyrrole (0.019 mole) was dissolved in water(40 ml) and the solution was treated with charcoal (0.1 g) and filtered.Chloroacetylchloride (0.067 mole) and aqueous NaOH (58.1 ml, 20% w/v)were added separately and simultaneously during 1 hour to the stirredsolution. The reaction mixture was maintained under an inert atmosphereand at room temperature for 1.5 hour. The compound of the title whichspontaneously crystallized out of the reaction mixture, was collected byfiltration.

(c) N-(4-benzoyl-1,5-dimethyl(1H)pyrrol-3-yl)2-chloroacetamide:

N-(4-benzoyl-5-methyl(1H)-pyrrol-3-yl)2-chloroacetamide (0.019 mole) wasdissolved in butan-2-one (60 ml) and K₂ CO₃ (4.5 g) and dimethylsulphate(0.037 mole) were added to the obtained solution. The reaction mixturewas maintained at the reflux temperature for 5 hours and at roomtemperature overnight. An inert atmosphere was maintained throughout theprocess. The inorganic salts were filtered off and the clear solutionwas evaporated under vacuum to yield a residue which uponcrystallization from methanol gave the compound of the title.

(d) N-(4-benzoyl-1,5-dimethyl(1H)pyrrol-3-yl)2-iodoacetamide:

N-(4-benzoyl-1,5-dimethyl(1H)pyrrol-3-yl)2-chloroacetamide (0.741 mole)and potassium iodide (1.62 mole) were refluxed in ethanol (3400 ml) for5 hours with stirring. The reaction mixture was then cooled, theinorganic salts were filtered off and the solvent was evaporated undervacuum. The obtained residue was purified by washing first with waterand then with cold ethanol. M.p. 135°-137° C. Yield 87%.

EXAMPLE 17N-(4-(2-chlorobenzoyl)-1,5-dimethyl(1H)pyrrol-3-yl)2-iodoacetamide

The compound of the title was prepared by following the proceduresdescribed in the foregoing example but starting from(2-chlorobenzoyl)acetone instead of benzoylacetone. M.p. 155°-57° C.

We claim:
 1. A pyrrolo[3,4-e][1,4]diazepin of the formula ##STR14##wherein R represents methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl, R₁ stands forhydrogen, methyl, ethyl, or phenyl, R₂ is hydrogen, methyl, ethyl,propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and1,1-dimethylethyl, and R₃ represents hydrogen, chloro, fluoro, bromo,trifluoromethyl and methoxy.
 2. A compound as in claim 1 wherein R ismethyl, R₁ is hydrogen, R₂ stands for hydrogen or methyl, and R₃represents hydrogen, chloro or fluoro.
 3. A compound as in claim 2wherein R is methyl, R₁ is hydrogen, R₂ stands for hydrogen or methyl,and R₃ is hydrogen or chloro.
 4. An intermediate compound of formula IV##STR15## or of formula V ##STR16## wherein R represents methyl, ethyl,propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and1,1-dimethylethyl, R₁ stands for hydrogen, methyl, ethyl or phenyl, R₂is hydrogen, methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl, and R₃ representshydrogen, chloro, fluoro, bromo, trifluoromethyl, and methoxy.
 5. Acompound as in claim 4 wherein R is methyl, R₁ is hydrogen, R₂ standsfor hydrogen or methyl, and R₃ represents hydrogen, chloro or fluoro. 6.A compound as in claim 5 wherein R is methyl, R₁ is hydrogen, R₂ standsfor hydrogen or methyl, and R₃ is hydrogen or chloro.
 7. Ananti-convulsant or anti-anxiety pharmaceutical composition consistingessentially of an inert pharmaceutical carrier and an effectiveanti-convulsant or anti-anxiety amount of a compound of claim
 1. 8. Ananti-convulsant or anti-anxiety pharmaceutical composition consistingessentially of an inert pharmaceutical carrier and an effectiveanti-convulsant or anti-anxiety amount of a compound of claim
 4. 9. Apharmaceutical composition as in claim 7 which contains from about 2.5to about 150 mg. of a compound of claim 1 together with apharmaceutically acceptable carrier.
 10. A pharmaceutical composition asin claim 8 which contains from about 2.5 to about 150 mg. of a compoundof claim 4 together with a pharmaceutically acceptable carrier.
 11. Acompound according to claim 1 which is5-(2-chlorophenyl)-1,7-dihydro-3-hydroxy-6,7-dimethylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one.12. A compound according to claim 1 which is5-(2-chlorophenyl)-1,7-dihydro-3-hydroxy-1,6,7-trimethylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one.13. A compound according to claim 4 which is5-(2-chlorophenyl)-3-acetoxy-1,7-dihydro-6,7-dimethylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one.